16-aminomethyl pregnenes



United States Patent lfi-AMINOMETHYL PREGNENES Raymond M. Dodson, ParkRidge, 12L, assignor to G. D. Searle & (10., Chicago, Ill., acorporation of Illinois No Drawing. Application August 13, 1954, SerialNo. 449,789

13 Claims. (Cl. 260-397.4)

My invention is concerned with lfi-aminoalkyl steroid derivatives and,more particularly, with 16-(a-aminoalkyl)-3-hydroxy-5-pregnen-20-onesand their acyl derivatives.

These compounds can be represented by the general structural formulawherein is a lower alkylene radical and R and R" are members of theclass consisting of hydrogen and lower hydrocarbon-carbonyl radicalscontaining 1 to 8 carbon atoms.

In the foregoing structural formula R can be hydrogen or a lower alkylradical such as methyl, ethyl, straightchained or branched propyl,butyl, amyl, or hexyl. The radicals R and R can be hydrogen or lowerhydrocarbon-carbonyl radicals derived from such lower hydrocarboncarboxylic acids as formic, acetic, propionic, butyric, valeric,caproic, benzoic, toluic, cyclohexanecarboxylic, cyclohexaneacetic,cyclopentanepropionic acids and the like.

These compounds are of therapeutic value because of their hormonalaction, particularly as progesterone inhibitors and as anti-inflammatoryagents. The compounds are particularly useful in conditions such asiritis. They are also valuable as intermediates in organic synthesis.Thus oxidation under Oppenauer conditions yields the corresponding4-pregnene-3,20-dione derivatives which likewise have valuable hormonalactivities and act as progesterone inhibitors.

The compounds of my invention are conveniently prepared by the methodsindicated in my copending application, Serial No. 362,955, filed June19, 1953 (now Patent No. 2,697,109). The present application is acontinuation-in-part of that application. Treatment of a 3-hydroxy or3-acyl0xy derivative of 5,16-pregnadien-20- one with a lower nitroalkaneof the structural formula in a mild base with an ionization constantgreater than 10* yields the 16-(a-nitroalkyl) derivative of thestructural formula on; 5 (Jib oo CH3 A CH-NO:

The nitro group is conveniently reduced to an amino group by treatmentwith iron and an acid such as hydrochloric or acetic acid. Acylation ofthe 3-hydroxy and of the amino group is accomplished by conventionalprocedures using the corresponding acid anhydrides and halides.

The compounds which constitute my invention and the methods for theirpreparation will appear more fully from the consideration of thefollowing examples. However, my invention is not to be construed aslimited by the details set forth in spirit or in scope. Quantities ofmaterials are indicated in parts by weight.

Example 1 A mixture of 356 parts of 3-acetoxy-5,lo-pregnadien- ZO-one,3500 parts of nitromethane and 600 parts of anhydrous piperidine ismaintained at room temperature for 5 days, concentrated to a smallvolume under vacuum and diluted with ether. The resulting solution iswashed thoroughly first with dilute potassium hydroxide and then withdilute hydrochloric acid, dried over anhydrous sodium sulfate, filteredand evaporated. Crystallization from a mixture of petroleum ether andbenzene using charcoal decolorization yields 3-acetoxy-16-nitro- 40methyl-S-pregnen-ZO-one melting at about 148149.5

C. An 0.32% chloroform solution shows a specific rotation of [a] '5.

Example 2 To a solution of 24.3 parts of3-acetoxy-16-nitromethyl-S-pregnen-ZO-one in 800 parts of methanol, asolution of 20 parts of potassium hydroxide in 150 parts of water isadded. After slight heating to etfect solution, the mixture is permittedto stand at room temperature for 5 hours. A small quantity of insolublematerial is then removed by filtration and the filtrate is neutralizedwith acetic acid. The resulting precipitate of 3-hydroxy-16-nitromethyl-S-pregnen-ZO-one is collected on a filter andrecrystallized from acetone. The product melts at about 225227 C. A 1%chloroform solution shows a specific rotation of [a] =+18.

Example 3 A mixture of 21 parts of 3-acetoxy-l6-nitromethyl-5-pregnen-ZO-one, 30 parts of iron filings, 200 parts of acetic acid and600 parts of water is heated under'reflux for 4 hours and then filtered.The ferrous hydroxide and the desired amine are precipitated by additionof ammonium hydroxide. The precipitate is separated by filtrationthrough a silica filter aid, dried and pulverized. The powder isextracted exhaustively with benzene. The benzene solution is filteredand thoroughly extracted with 10% acetic acid. This extract is madealkaline by addition of ammonium hydroxide. The resulting precipitate iscollected on a filter, dried in an oven and crystallized from dilutemethanol. The 3-acetoxy-16-aminomethyl-5- pregnen-ZO-one thus obtainedmelts at about 162-163 C.

TCHrNHz Example 4 A solution of 2 parts of 3-acetoxy-l6-aminomethyl-5-pregnen-ZO-one in 80 parts of methanol and 2 parts of potassiumhydroxide in 10 parts of water is heated at reflux temperature for 2hours and then filtered. The filtrateis poured into water and the3-hydroxy-l6-aminomethyl-S- regnen-ZO-One is salted out by addition ofsodium chloride. After crystallization from a mixture of benzene,ethanol and cyclohexane, and then from highly dilute methanol, crystalsare obtained which melt at about l8919l C. with resolidification. Theidentical product is obtained by treatment of3-hydroxy-16-nitromethyl-5- pregnen-20-one with iron and acetic acid bythe procedure of the preceding example. The compound has the structuralformula =0 CHO GET-NH,

7 Example A solution of 186 parts of 3-acetoxy-16-aminomethyl-S-pregnen-ZO-one in 1000 parts of pyridine is treated with 1080 parts ofacetic anhydride, permitted to stand for 10 hours and then poured intocold water. The resulting precipitate is collected on a filter andcrystallized from dilute methanol. The3-acetoxy-16-acetylaminomethyl-5-pregnen-20-one thus obtained melts atabout 167-170 C. It has the structural formula solution of 5 parts of3-acetoxy-l6-acetylaminomethyl-S-pregnen-ZO-one in 200 parts of methanolis treated with a solution of 5 parts of .potassiumhydroxide in 50 partsof water. After standing for 10 hours at room temperaturejthe reactionmixture is filtered and the filtrate is neutrali zed with 5 parts ofdilute acetic acid, heated 4 e a and diluted with water. Upon coolingthe 3-hydroxy-16- acetylaminomethyl-S-pregnen-20-one precipitates,which, recrystallized from dilute methanol, melts at about 232- 233 C. A1% chloroform solution shows a specific rotation of [a] =+6. Thecompound has the structural formula CHa 50 CH3 CHz-NHC O-C HI Example 7A solution of 13 parts of cyclohexanecarbonyl chloride and 5 parts of3-acetoxy-16-aminomethyl-5-pregnen-20- one in 30 parts of pyridine iskept at 25 C. for 30 minutes. The reaction mixture is then poured intocold water whereupon the 3-acetoxy-16-cyclohexanecarboxyl-aminomethyl-5-pregnen-20-one separates as an oil. The compound has the structuralformula CH: p

A CHg-NH-G O-GH (CH1): I

CHI-CO0 methyl-S-pregnen-ZO-one thus obtained melts at about 210-2115 0.The specific rotation of an 0.6 chloroform solution is +l6.7. Thecompound has the formula (6H: CO CH:

Example 8 A mixture of 5.8 parts of S-acetoxy-16-aminomethyl-5--pregnen-ZO-one, 30 parts of pyridine and 12 parts of benzoyl chloride ismaintained at room temperature for an hour and then poured into 200parts of ice water. 50 parts of 4-N sodium hydroxide are added and themixture is allowed to stand for 3 hours with occasional warming andstirring. The 3-acetoxy-l6-benzoylaminomethyl-5- pregnen-ZO-one iscollected on a filter and washed with water. The compound has thestructural formula CHa-C O Example 9 The product obtained in thepreceding example is stirred with 160 parts of methanol, 240 parts ofethanol and 100 parts of dioxane and treated with a solution of 6 partsof potassium hydroxide in 15 parts of water. Stirring is continued forten hours after which the suspension is filtered and the filtrate isneutralized with glacial acetic acid. The filtrate is evaporated undervacuum to about one-third of its original volume and then diluted withwater until crystallization starts. The precipitate is collected on afilter, dissolved in acetone, stirred with charcoal, filtered andtreated with cyclohexane to yield 3-hydroxy-16-benzoylaminomethyl-S-pregnen-20-one which melts at about l78179.5 C. Theultraviolet absorption spectrum shows a maximum at 227 millimicrons witha molecular extinction coeflicient of 10,850. The specific rotation of a0.341% chloroform solution is +689. The compound ture is made basic byaddition of dilute ammonium hydroxide and the resulting precipitate isremoved by filtration through a silica filter aid. The precipitate isdried, pulverized and thoroughly extracted with boiling benzene. Thebenzene solution is exhaustively extracted with dilute acetic acid andthe extract is made alkaline by addition of ammonium hydroxide. Theprecipitate thus obtained is collected on a filter, dried andcrystallized from dilute methanol to yield3-benzoyloxy-l6-aminomethyl-5-pregnen-ZO-one which has the structuralformula C=O CH:

The compound does not melt sharply because of polymerization.

Example 11 A solution of 56 parts of 3-benzoyloxy-l6-aminomethyl-S-pregnen-ZO-one in 400 parts of pyridine is treated with 100 parts ofcyclopentaneacetyl chloride. After standing at room temperature for anhour, the reaction mixture is poured into ice Wate. The resultingprecipitate is collected on a filter and crystallized from dilutemethanol. The 3benzoyloxy-l6-cyclopentaneacetylaminomethyl-5-pregnen-20-one thusobtained has the structural formula C 0 CH3 CH2NHC O-CHz-CH (CH1)4 COCH;

Example 10 A solution of 43 parts of 3-benzoyloxy-5,16-pregnadien-20-one, 500 parts of nitromethane and 200 parts of anhydrous piperidineis maintained at C. for 100 hours, warmed to 50 C. and then evaporatedunder vacuum to a small volume. The residue is diluted with ether andbenzene. This solution is washed thoroughly with dilute potassiumhydroxide and then with hydrochloric acid to remove all of thenitromethane and piperidine remaining. The residue is dried overanhydrous sodium sulfate, stirred with decolorizing charcoal, filteredand evaporated to yield the 3-benzoyloxy-l6-nitromethyl-5-pregnen-20-one. The compound is readily crystallized from ethyl acetate or acetone.It shows a double melting point; it first melts at about 205-207" C.,resolidifies and melts again at about 211-212 C.

A mixture of 47 parts of this compound, 60 parts of iron filings and1000 parts of water is refluxed for 3 hours. During the first 90minutes, 260 parts of acetic acid are added portion-wise to control thereaction rate. The mix- The infrared absorption spectrum shows maxima at2.89, 6.01 and 6.57 microns in chloroform solution.

Example 12 A mixture of 357 parts of 3-acetoxy-5,l6-pregnadien- 20-one,3150 parts of nitroethane and 600 parts of anhydrous piperidine ismaintained at room temperature for a week, concentrated under vacuum toa small volume and diluted with ether and a small amount of benzene. Theresulting solution is washed successively with dilute potassiumhydroxide, water, dilute hydrochloric acid, and again with water,stirred with charcoal, filtered, dried over anhydrous sodium sulfate,again filtered and evaporated. Crystallized from dilute methanol andthen from cyclohexane, the 3-acetoxy-l6-(a-nitroethyl)-5-pregnen- ZO-onethus obtained melts at about 156166 C. The specific rotation of a 1%chloroform solution is +175".

To a solution of 98 parts of this product in 4000 parts of methanol isadded a solution of 100 parts of potassium hydroxide in 1000 parts ofwater. After standing at room temperature for 12 hours, the mixture isfiltered and the filtrate is neutralized with acetic acid. The mixtureis then heated, diluted with water and cooled and the3-hydroxy-16-(a-nitroethyl)-5-pregnen-20-one is collected on a filter.The crystals thus obtained melt at about l54l59 C.

A mixture of 37 parts of 3-hydroxy-l6-(a-nitroethyl)- S-pregnen-ZO-one,60 parts of iron, 260 parts of acetic acid and 1000 parts of water isrefluxed for minutes and then filtered. The filtrate is renderedalkaline by addition of ammonium hydroxide and the precipitate isseparated by filtration through a silica filter aid. The

residue is dried, pulverized and then thoroughly extracted with diluteacetic acid. The extract is rendered alkaline by addition of ammoniumhydroxide. The resulting precipitate of3-hydroxy-16-(a-aminoethy1)-5-pregnen-20- one thus obtained isrecrystallized from highly diluted methanol. Thecompound has thestructural formula The ultraviolet spectrum shows no appreciableabsorption between 222 and 320 millimicrons.

Example 13 A solution of parts of3-hydr0xy16-(a-aminoethyl')-5-pregnen-20 one in 1000 parts of pyridineand 1000 parts of butyric anhydride is permitted to stand at roomtemperature for a day and then poured into ice water. The resultingprecipitate is collected on a filter and crystallized repeatedly fromdilute methanol to" yield the 3-butyroxy-l6-(a-butyrylaminoethyl)-5-pregnen-ZO-one in white prisms. The infrared absorption spectrum inchloroform shows maxima at 2.89, 5.80, 5.90, 6.01 and 6.57 microns. Thecompound has the structural formula A solution of 24.3 parts of3-hydroxy-16-acety1amino methyl-5-pregnen-20-one in 865 parts of tolueneand 280 parts of cyclohexanone is concentrated to. 42% of its originalvolume and then treated with a solution of 30' parts of aluminumisopropoxide in 130 parts of.

toluene. After being heated under reflux for one-half hour, the mixtureis poured into 1000 parts of a saturated Rochelle salt solution, Thissolution is then extracted with ethyl acetate and the ethyl acetateextract is washed thoroughly with Rochelle salt solution. The Rochellesalt solutions are once more extracted with ethyl acetate and theorganic layers are combined and washed thoroughly with water.Concentration to a small volume and dilution with petroleum ether causesprecipitation of 16-acetylaminomethyl-4-pregnene-3,20-dione which,recrystallized from dilute methanol, melts at about 219-220 C. 7

Example A mixture of 4 parts of 3-hydroxy-16-cyclohexanecarboxylaminomethyl-S-pregnen--one, 40 parts of toluene, 30 parts ofcyclohexanone and a solution of 3 parts of aluminum isopropoxide in 15parts of toluene is heated under reflux for 20 minutes, poured into 100parts of a saturated Rochelle salt solution and steam distilled. Theresidue is extracted with ethyl acetate. The extract is concentrated andthe residue'applied in benzene to a chromatography column containing 400parts of silica gel. The column is washed with benzene and then withbenzene solutions containing increasing proportions of ethyl acetate.Elution of the column with 21-40% solution of ethyl acetate in benzeneand trituration of the-resulting eluates with ether causes precipitationof l6-cyclohexanecarboxylaminomethyl-4-pregnene 3,20- dione. Oncrystallization from dilute acetone, crystals are obtained which melt atabout 105-110 C. The specific rotation of a 1.1% chloroform solution is+136. An ultraviolet absorption maximum is observed at 240 millimicronswith a molecular extinction coeflicient of Example 16 An anhydroussolution of 4 parts of 3-hydroxy-l6-benzoylaminomethyl-S-pregnen-20-onein 40 parts of toluene and 30 parts of cyclohexanone is treated with asolution of 3 parts of aluminum isopropoxide in 15 parts of toluene andthen heated at reflux for 20 minutes. The mixture is then poured intoparts of a saturated solution of Rochelle salt and steam-distilled. Theresidue is cooled and the precipitate collected on a filter. The productthus wherein is a lower alkylene radical and R and R" are members of theclass consisting of hydrogenand lower hydrocarboncarbonyl radicalscontaining 1 to 8 carbon atoms.

2. A compound of the structural formula r Co CH3 (lJH -NH1 R wherein Ris a lowerhydrocarbomcarbonyl radical con-.

taining 1 to 8 carbon atoms and is a lower alkylene radical.

3. A compound of the structural formula I GO 4.3-acetoxy-1G-aminomethyl-S-pregnen-ZO-one. 5. A compound of thestructural formula is a lower alkylene radical.

6. 3-hydroXy-16-acetylaminomethyl-S-pregnen-20one. 7. A compound of thestructural formula R is a lower alkylene radical.

8. 3 hydroxy 16 cyclohexanecarboxylaminomethyl- S-pregnen-ZO-one.

9. A compound of the structural formula is a lower alkylene radical.

10. 3 hydroxy 16 benzoylaminomethyl 5 pregnen20-one.

11. A compound of the structural formula wherein wherein R and R arelower hydrocarbon-carbonyl radicals containing 1 to 8 carbon atoms andis a lower alkylene radical.

12. A compound of the structural formula is a lower alkylene radical.

13. 3 acetoxy 16 acetylaminomethyl 5 pregnen- 20-one.

References Cited in the file of this patent UNITED STATES PATENTS JulianJuly 31, 1951 Julian Mar. 11, 1952

1. A COMPOUND OF THE STRUCTURAL FORMULA